Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo.
Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo.
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DOI：
10.1172/jci18377
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发表时间：
2003-08
期刊：
影响因子：
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通讯作者：
N. Shibusawa;Koshi Hashimoto;K. Hashimoto;A. Nikrodhanond;M. Liberman;M. Applebury;X. Liao;J. Robbins;S. Refetoff;R. Cohen;F. Wondisford
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文献类型：
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作者：
N. Shibusawa;Koshi Hashimoto;K. Hashimoto;A. Nikrodhanond;M. Liberman;M. Applebury;X. Liao;J. Robbins;S. Refetoff;R. Cohen;F. Wondisford
甲状腺激素的作用是由甲状腺激素受体介导的，甲状腺激素受体是核激素受体超家族的成员。dna结合被认为是甲状腺激素所有核作用的必要条件。为了在体内验证这一假设，利用基因靶向技术在tr - β的P-box （GS突变体）内突变dna结合域。这种突变在体外完全消除了tr - β dna结合，同时保留了配体（T3）和辅因子与受体的相互作用。纯合突变体（tr - β -/-）小鼠显示下丘脑-垂体-甲状腺轴和视网膜的异常T3调节，与之前在tr - β - KO （tr - β -/-）小鼠中观察到的异常相同。然而，与tr - β -/-小鼠相比，tr - β -/-突变小鼠在某些频率下保持正常听力，未表现出明显的外毛细胞损失。因此，dna结合对TR的许多功能至关重要，包括视网膜发育和下丘脑-垂体-甲状腺轴甲状腺激素的负反馈调节。内耳发育，虽然不是完全正常的，但可以在没有TR dna结合的情况下发生，这表明另一种可能是新的甲状腺激素信号通路可能介导这些作用。
Thyroid hormone action is mediated by thyroid hormone receptors (TRs), which are members of the nuclear hormone receptor superfamily. DNA-binding is presumed to be essential for all nuclear actions of thyroid hormone. To test this hypothesis in vivo, the DNA-binding domain of TR-beta was mutated within its P-box (GS mutant) using gene targeting techniques. This mutation in vitro completely abolishes TR-beta DNA-binding, while preserving ligand (T3) and cofactor interactions with the receptor. Homozygous mutant (TR-betaGS/GS) mice displayed abnormal T3 regulation of the hypothalamic-pituitary-thyroid axis and retina identical to abnormalities previously observed in TR-beta KO (TR-beta-/-) mice. However, TR-betaGS/GS mutant mice maintained normal hearing at certain frequencies and did not display significant outer hair cell loss, in contrast to TR-beta-/- mice. DNA-binding, therefore, is essential for many functions of the TR, including retinal development and negative feedback regulation by thyroid hormone of the hypothalamic-pituitary-thyroid axis. Inner ear development, although not completely normal, can occur in the absence of TR DNA-binding, suggesting that an alternative and perhaps novel thyroid hormone-signaling pathway may mediate these effects.